A scientific silver lining

Researchers were aiming to find a genetic solution to a rare and devastating disease but were not able to identify one. However, in the process they identified a crucial factor in one of life’s most essential processes.

Professor Carl Walkley and his team were trying to identify new pathways that could be used to treat Rothmund-Thomson Syndrome (RTS) Type II, a very rare condition which includes low bone mass and immune compromise, as well as a greatly increased rate of cancer, particularly osteosarcoma.

Systematically switching off genes

They used cell lines derived from a mouse model with mutations similar to those identified in RTS patients and systematically blocked every other gene, looking for one which would “make up for” the effects of the mutation that causes RTS. What they found surprised them.

“We found only one gene where we saw a difference, but there was a catch,” Prof Walkley said. “It’s a really accurate result, but the result was purely a product of the fact we’d used mouse cell lines, so it doesn’t end up being applicable to humans with RTS.”

“What that meant was, in this study, we could not find a pathway to target that could potentially have made a difference for RTS patients – however that one pathway we did find actually provided important new information about the way DNA divides and multiplies in every cell in everybody.”

Crucial to cell division

The pathway found relates to a protein called RECQL4. Mutations in this protein are a cause of Rothmund-Thomson Syndrome Type II.

The RECQL4 protein is crucial to the process of DNA replication and cell division – if it is lost completely, this causes cell death. But particular shorter forms of RECQL4 are still functional, so its exact role in the cell, and how it works, is unknown.

In their study, Prof Walkley and the team identified for the first time that just very low levels of a shortened form of the RECQL4 protein will maintain the ability of cells to divide. Their findings demonstrate how these shorter forms of the protein can still work to support DNA replication, and advances our overall understanding of how RECQL4 functions.

“Previous studies had suggested that cell division was possible without RECQL4, but we have now been able to confirm its vital role in this process, even if it’s only there in trace amounts.” he said.

And while this study did not find a pathway to circumvent the effects of RECQL4 mutation in RTS, it does suggest that specific targeting of the disease-causing mutations may be a way forward instead – providing potential future avenues to be explored.